Quaternary ammonium salts of tertiary-aminoalkyl 4-substituted-2-(tertiary-aminoalkoxy) benzoates and their preparation



Patented June 16, 1953 QUATERNARY AMMONIUM SALTS OF TER- TIARY-AMINOALKYL 4, SUBSTITUTED-2- (TERTIARY AMINOALKOXY BENZOATES AND THEIR PREPARATION Raymond 0. Clinton, North Greenbush, and Stanley 0. Laskowski, Menan'ds, N. Y., assignors to Sterling Drug Inc., NewYork, N. Y., a corporation of Delaware No Drawing. Application September 5, 1951, Serial No. 245,249

24 Claims.

This invention relates to quaternary ammonium salts of tertiary-aminoalkyl 4-substituted- 2-(tertiary-aminoalkoxy)benzoates and to their synthesis.

The quaternary ammonium salts of our invention have the general formula Where Z is nitro or amino, X and Y are each lower alkylene radicals, N'RRi and NRzRa are each tertiary-amino radicals, R5 is a lower alkyl radical or benzyl radical and An is a non-toxic anion. These compounds of our inventionhave useful pharmacological properties, such as, ganglionic blocking activity.

In the above general formula, the lower alkylene radicals designated as X and Y each has two to four carbon atoms and each has its'two free valence bonds on different carbon atoms. Thus, X and Y include such examples as -CH2CH2,

-CH2CH2CH2,

-CH2CH2Cl-I2CH2, CH2CH(CH3)CH2-, and the like. For a given compound, the lower alkylene radicals X and Y can be alike or difierent. The tertiary-amino radicals, shown above as NRR1 and NRzRB, each comprehend dialkylamino radicals where R, R1, R2 and R3 are lower alkyl groups, alike or different, and each alkyl group has one to six carbon atoms, such d alkylamino radicals including dimethylam1no, d1- ethylamino, ethylmethylamino, diisopropylam no, ethyl-n-propylamino, di-n-butylamino, di-nhexylamino, and the like. Further, the tertiaryamino radicals designated as NRRI and NRzl'tz each encompassed saturated N -heteromonocycl1c radicals having five to six ring atoms, illustrated by examples such as l-piperidyl; (lower alkylated)-1-piperidyl such as 2-methyl-1-piperidyl, 3 -ethyl-l-piperidyl, l-methyl-l-piperidyl, 2,6- dimethyl-l-piperidyl; l-pyrrolidyl; (lower alkylated) -1-pyrrolidyl such as Z-methyl-l-pyrrolidyl, 2,5-dimethyl-l pyrrolidyl; 4-morpholinyl; and the like. For a given compound, NRR1 and NRaRs can be alike or diiTerent. R5 when representing lower alkyl has preferably one to six carbonatoms, including such radicals as methyl, ethyL-n-propyl, n-butyl, isobutyl, n-amyl, n-hexyl, and the like. The non-toxic anion, designated above as An, which can be any anion, for instance, chloride, bromide, iodide, sulfate, benzenesulfonate, para-toluenesulfonate, and the like, has no appreciable pharmacological activity of its own in the high dilutions at which the quaternary ammonium salts as a Whole are effective. In particular,the anions contribute nothing to the ganglionic blocking activity which resides solely in the remainder of the molecule.

Thus, our invention comprehends quaternary ammonium salts of the above defined tertiaryaminoalkyl 4 substituted-2-(tertiary-aminoalkoxy)-benzoates, said salts being derived from lower alkyl or benzyl esters of an acid, either inorganic or organic, such esters having the formula R5An and including methyl iodide, methyl bromide, ethyl chloride, ethyl bromide, ethyl sulfate, n-propyl iodide, benzyl chloride, methyl para-toluenesulfonate, ethyl para-toluenesulfonate, ethyl benzenesulfonate, and the like, the respective quaternary salts being the methiodides, methobromides, ethochlorides, ethobromides, ethosulfates, 11,- propiodides, benzochlori'des, metho para-toluenesulfonates, etho-para-tolu-. enesulfonates, ethobenzenesulfonates, and the like.

The parent tertiary-aminoalkyl i-substituted- Z-(tertiary-aminoalkoxy) benzoates, are disclosed and claimed in our copending application Serial Number 245,246, filed September 5, 1951, and they can be prepared preferably according to the procedure represented by the following series of equations where X, Y, NRR and NR2R3 are de- 3 fined as above, R4 is a lower alkyl radical preferably having one to six carbon atoms and halogen is chlorine, bromine, iodine or fluorine:

I halogen-X-NRR; OH OX-NRR,

C 0 0 R4 0 OR;

is haloalkylated by treating its sodium salt with 2-chloroethyl para-toluenesulfonate to form ethyl 4-nitro-2-(2-chloroethoxy)benzoate which N02 QO-X-NRR;

OOH

halogen-Y-N R R;

In step I, a lower alkyl l-nitro-2-hydroxyben zoate (A) is converted into a lower alkyl 4-nitro- 2-(tertiary-aminoalkoxy) benzoate (C) by reaction with a tertiary-aminoalkyl halide (B). In

step II, the lower alkyl 4-nitro-2- (tertiary-amino- 39 ries of reactions is illustrated as follows: Ethyl 4-nitro-2-hydroxybenzoate, preferably in the form of an alkali metal salt, is reacted with a 2-diethylaminoethyl halide, preferably the chloride, to yield ethyl 4-nitro-2-(Z-diethylaminoethoxy) benzoate; this ethyl ester is saponified to yield the corresponding acid; the acid is treated with 2-(l-piperidyl)ethyl halide to form 2- (l-piperidyl) ethyl 4-nitro-2- (2-diethylaminoethoxy)benzoate; and this -nitro ester is reduced to form the corresponding 2-(1-piperidyl) ethyl 4 amino 2 (2 diethylaminoethoxy) benzoate.

Step I is carried out preferably using a lower alkyl 4-nitr0-2-hydroxybenzoate in the form of a metal derivative, with a tertiary-aminoalkyl halide. Alternatively, step I can be carried out using a lower alkyl l-nitro-2-hydroxybenzoate itself, however, with a resulting decrease in yield of the lower alkyl 4-nitro-2-(tertiary-aminoalkoxy)benzoate. The lower alkyl 4-nitro-2- (tertiary-aminoalkoxy)benzoates (C) are disclosed and claimed in our copending application Serialm-No. 254,244, filed September 5, 1951.

Step I is also carried out stepwise, that is, bl

first haloalkylating the lower alkyl 4-nitro-2- hydroxybenzoate (A) to form the lower alkyl 4-nitro-2-(haloalkoxy)benzoate which is then treated with a secondary amine having the formula I-lNRRi. The first step can be accomplished by treating a lower alkyl 4-nitro-2-hydroxybenzoate or a metal derivative thereof with a haloalkylating agent such as a haloalkyl paratoluenesulfonate, haloalkyl benzenesulfonate, dihaloalkane, etc. As illustrations of this stepwise procedure, ethyl 4-nitro-2-hydroxyzenzoate lIII OO-Y-NR Ri i V then is treated with diethylamine or piperidine to form ethyl 4-nitro-2-(2-diethylaminoethoxy) benzoate or ethyl 4-nitro-2-[2-(1-piperidyl)- ethoXy] benzoate, respectively.

The esterification step III is carried out preferably by heating a 4-nitro-2-(tertiary-aminoa1koxy)benzoic acid with a tertiary-aminoalkyl halide. In practice we found this reaction could be satisfactorily and conveniently carried out in refluxing propanol or ethanol using the 4-nitro- 2- (tertiary-aminoalkoxy) benzoic acid in the form of its hydrochloride addition salt (alternatively, the free base form can be used) and using a tertiary-aminoalkyl chloride.

The reduction step IV is carried out either by chemical methods or by catalytic hydrogenation. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate and 1 ammonia, tin and hydrochloric acid, sodium hydrosulfite, etc. In practicing our invention, We used preferably iron and hydrochloric acid. Catalysts suitable when catalytic hydrogenation is employed include Raney nickel, platinum,

l5 palladium or other catalysts generally effective to catalyze hydrogenation of nitro groups to amino groups.

The quaternary ammonium salts of our present invention are prepared preferably according 3 to the process as illustrated for the methiodides by the following series of equations where X, Y, NRRi and NRzRs are defined as above:

5. in step V, a tertiary-aminoalkyl 4-nitro-2-(tertiary-aminoalkoxy) benzoate (F) is treated with methyl iodide to yield the corresponding tertiary aminoalkyl 4 nitro 2 (tertiary aminoalkyDbenzoate dimethiodide(H). In step VI, the l-nitro dimethiodide (H) is reduced to yield the corresponding tertiary-aminoalkyl a-amino- 2- (tertiary-aminoalkoxy) benzoate dimethiodide (J). As a specific illustration of this series of reactions, 2-diethylaminoethyl 4-nitro-2-(2'-diethylaminoethoxy) benzoate is treated with methyl iodide to form Z-diethylaminoethyl 4- nitro 2 (2 diethylaminoethoxy) benzoate dimethiodide, which is then reduced to yield the corresponding Z-diethylami'noethyl l-amin'o 2- (2-diethylaminoethoxy)benzoate dimethiodide.

When, in step V, other lower alkyl or benzyl esters of an acid are substituted for methyl iodide, the corresponding l-nitro (H) and Jr-amino (J) quaternary salts are formed. Other lower alkyl and benzyl esters that are suitable include those of the type shown hereinabove.

.The reduction step V1 is carried out preferably by catalytic hydrogenation using such catalysts as Raney nickel, platinum, palladium -or other catalysts generally effective to catalyze hydrogenation of nitro groups to amino groups. Alternatively, but less desirably, this reduction step can be carried out by chemical methods. Suitable chemical reducing agents include iron and a hydrohalic acid, tin and a hydrohalic acid, etc.

Alternatively, but less preferably, the tertiaryaminoalkyl 4-amino-2-(tertiary-aminoalkoxy) benzoate quaternary salts can be prepared by treating, preferably at room temperature, the corresponding tertiary-aminoalkyl 4-amino-2- (tertiary-aminoalkoxy) benzoates, designated above as (G), with an alkyl or benzyl ester of an inorganic or organic acid of the type described hereinabove. Thus, treatment of 2-dimethylaminoethyl 4-amino-2- [3- l-pyrrolidyl) propoxylbenzoate with methyl iodide or-benz'yl chloride results in the formation of 2-dimethylaminoethyl l-amino 2 [3-(l-pyrrolidyl) propoxylbenzoate dimethiodide or 2-dimethylaminoethyl 4-amino-2- [3- (l -pyrrolidyl) propoxy] benxoate dibenzochloride, respectively. This mode of preparation is not as desirable as the foregoing described method of reducing the corresponding tertiary-aminoalkyl 4-nitro-2-(tertiary-aminoalkoxy)'benzoate quaternary ammonium salts since here some alkylation of the Jr-amino radical might result, as a competing reaction. Alkylation of the 4-amino radical is effected by heating the mixture of reactants in the presence of a hydrogen halide acceptor.

The following examples illustrate specific embodiments of our invention.

(1) Lower alkyl 4-nitro-2 (tertidrgj-Einiioallcoxy) beneoates Preparation of the lower alkyl 4-nitro-2-(tertiary-aminoalkoxy) benzoates is illustrated by the following alternative procedures, all of which involve alkylation of a lower alkyl 4-n'itro-2-hydroxybenzoate or a metal salt thereof with a tertiary-aminoalkyl halide, or, stepwise, with a haloalkylating agent such as a haloalkyl para-toluenesulfonate to produce a lower alkyl 4-nitro-2- (haloalkoxy) benzoate which is then treated with a secondary amine to form the desired lower alkyl 4-nitro-2- (tertiary-aminoalkoxy) benzoate.

Ethyl 4-nitro-2- (2-diethylaminoethoxy) benzoate was'prepared as follows: 'Io a stirred reflux-'- absolute ethanol. tion was added, with stirring over a period of about twenty minutes, 27.1 g. of 2-diethylamin'oethyl chloride and the resulting mixture was .refluxed for about three hours. An additional 5 g. of 2-diethyla'minoethyl chloride was then added and refluxing continued for an additional thirty The reaction mixture was cooled in.

minutes. ice, filtered, and the filtrate taken to dryness in vacuo The residue was taken up in 500 ml. of

ethyl acetate, the resulting solution filtered'an'd;

the filtrate taken to dryness, yielding ethyl 4 -'nitro 2 (2 diethylaminoethoxy) benzoate,

This compound was converted into its hydrochloe ride addition salt by dissolving it in a small amount of ethyl acetate and treating the solution with an excess of 20% ethereal hydrogen chloride solution. The resulting precipitate of ethyl 4 nitro-2- (2-diethylaminoethoxy) benzoate hydrochloride was collected and recrystallized twice from isopropanol, yielding 45.5 g. of purified product, M. P. 144.4-145.2 C. (cor.).

AnaZ.--Calcd. for C15H22NzOs-HCl:- C, 51.94; I-I,6.40; Cl, 10.22. Found: C, 52.08; H, 6.48; Cl, 10.12.

Ethyl 4-nitro-2- (2-diethylaminoethoxy) benzoate was also prepared stepwise as follows: A mix ture of 84.4 g. of ethyl 4-nitro-2-hydroxybenzoe ate, 60.8 g. of powdered anhydrous potassium carbonate and Z000ml. of meta-xylene was refluxed with stirrin under a water trap until no more water was collected (three hours). The water trap was removed and 112.7 g. of 2-chloro-v ethyl para-toluenesulfonate was added in one portion. Refluxing and stirring were continued for an additional nineteen hours. The mixture was filtered while hot and the filter-cake was washed with hot toluene. The combined filtrate and washings were evaporated into dryness in vacuo, yielding a cream-colored solid as residue. Several recrystallizations of this solid from methanol and from n-pentane gave a 60% yield of ethyl 4-nitro-2-(2-chloroethoxy) benzoate as pale yellow platelets, M. P. 56.6-57.2 C. (cor.).

Anal.-Calcd. for C11H12C1NO5: C1, Found: Cl, 12.62.

On heating a mixture of ethyl -4-nitro-2-(2- chloroethoxy)benzoate, diethylamine, sodium iodide andabsolute ethanol, there was obtained,

in only a fair yield, ethyl 4-nitro-2-(2-diethylaminoethoxy)benzoate. Following this same procedure but using dimethylamine or 2-methylpiperidine inplace of diethylamine, there is obtained, ethyl 4-nitro-2-(Z-dimethylaminoethoxy)benzoate or ethyl l-nitro-2-[2-(2-methyl-1- piperidyl) ethoxylbenzoate, respectively.

.. .Ethyl 4-nitro-2 -.[3-.(1-.pipericlyl) propoxylbenzoate was prepared as follows: To a stirred refluxing solution of 84.4 g. of ethyl 4-nitro-2-.

hydroxybenzoate in 1500 ml. o'f'absolute ethanol was added in a fine stream a solution of 9.2g. of sodium in 500 ml. of absolute ethanol. To the resulting solution was added 'dropwise over a period of fifteen minutes 65 g. of 3-(1-piperidy1) propyl chloride and the resulting solution was refluxed for twenty-four hours. The sodium chloride was filtered off and washed with'ethyl acetate. The combined filtrate and washings were taken down to dryness under reduced pressure yielding a mixture of an oily residue and "a small amount of a red solid. To this mixture was added 2 liters of ether and'the insoluble 'red solid was filtered oil. The filtrate was evaporatedto dryness under reduced pressure, yielding, as an oily material, ethyl 4-nitro-2-[3-(1-piperidyl) propoxylbenzoate. This ester was converted into its hydrochloride salt by dissolving it in a little ethyl acetate and adding to the solution an excess of ethanolic hydrogen chloride. The solid hydrochloride separated slowly. The mixture was diluted with absolute ether, cooled, and the precipitate was collected and washed with absolute ether. The precipitate was recrystallized three times from isopropanol, yielding, as pale yellow needles, ethyl 4-nitro-2-[3-(l-piperidyl) propoxylbenzoate hydrochloride, M. P. 160.4- 161.6 C. (c012).

AnaZ.-Calod. for C17H24N2O5-HCI: N Cl, 9.51. Found: N 7.37; Cl, 9.33.

N1 1; stands for total nitrogen as determined by the Dumas met od.

n Butyl 4 nitro 2 (2 diethylaminoethoxy)benzoate was prepared as follows: To a stirred refluxing solution of 9.2 g. of sodium in 2000 m1. of n-butanol was added 95.7 g. of nbutyl 4-nitro-2-hydroxybenzoate. The red insoluble sodium phenclate separated immediately. After addition had been complete, refluxing was continued for an additional ten minutes, and then 54.2 g. of 2-diethy1aminoethyl chloride was added dropwise over a period of about twenty minutes. When the addition had been completed, the color had already changed from a deep red to a pale orange-yellow. The reaction mixture was then refluxed for five hours, cooled and filtered. The filtrate was taken down to dryness under reduced pressure yielding an oily residue and a small amount of red solid. This mixture was treated washed with absolute ether. Three recrystallizations of this solid from ethyl acetate yielded, as pale yellow needles, n-butyl 4-nitro-2-(2-diethylaminoethoxy) benzoate hydrochloride, M. P. 117.6- 1 18.6 C. (0012).

Anal.Calcd. for C17H2sN2O5-HC1: ND, 7.47; o1,

9.46. Found: N15, 7 .66; Cl, 9.44.

Ethyl 4 nitro 2 (2 dimethylaminoethoxy) benzoate was prepared as follows: To a solution of 126.6 g. of ethyl 4-nitro-2-hydroxybenzoate in 1000 ml. of absolute ethanol was added a solution of 13.8 g. of sodium in 500 ml. of absolute ethanol. The ethanol was then removed by distillation while simultaneously adding toluene.

Treatment of an ethyl acetate solution of this compound with an excess of 20% ethereal hydrogen chloride gave a gummy precipitate, which crystallized from isopropanol in pale yellow needles, M. P. 202.2202.6 C. (cor.). This product was ethyl 4-nitro-2-(2-dimethylaminoethoxyl) benzoate hydrochloride.

AnaZ.Calcd. for CiaI-IisNzOs-Hcl: ND, 8.79; CI, 11.12. Found: ND, 8.56; Cl, 11.10. 7

Additional lower alkyl 4-nitro-2-(2-tertiaryaminoalkoxy) benzoates prepared according to the abcvedescribed procedures are given in Table I.

TABLE 1' 0 cHomRm-Hm Analyses 1. NR R1 R. 2 Formula ND 01 Calcd. Found Calcd. Found 2' NCqHu CHzCHs 153. 0-154. 0 CmHzaNzOaHCl 7.24 7. 15 9. 16 9. 14 2 NCiHgO CHzCHg 207. 0-208. 0 CrsHzoNzOaHCl 7. 77 7. 81 9. 83 9. 92. 3 NC4H5O CHzCH; 142. -144. 6' CmHzzNzOaHCl 7. 48 7. 79 9. 46 9. 25 2 NCsHm CHZOHIA 191. 0-191. 5 CwHzzNzOsHC] 7. 81 7. 82 9. 88 9. 90 2 NCflEIIaO CH3 206. 0-206. 4 Ci4H1sNzOn.HC1 B 4. 04 e 4. 05 10. 22 10.21 2 NCaHm CHzCHa 180. 8-182. 6 C17H24N205.HC1 7. 52 7. 22 9. 51 9. 38 3 NCaHn CHzCHs 158. 2-159. 6 C aH2cN2O5.HCl 7. 24 7. O3 9. 16 8. 92 3 N(O2H5)z CHzOHa 164. 8-165. 6 G16H24N205.HC1 7. 77 7. 87 9. 83 9. 72 2 N(CzH5)z CHzCHzCHB 153. 4-155. 4 CmH24N2O5.HC1 7. 77 7. 95 9. 83 9. 83 2 N(G2Hs)2 CH3 156. 9-159. 2 OHH20N205.HC1 8. 42 8. 38 10. 9 10. 50

with 2500 ml. of absolute ether, and the red solid was filtered off. The filtrate was taken down to dryness under reduced pressure, yielding, as an oil, the product, n-butyl 4-nitro-2-(2-diethy1- aminoethoxy) benzoate. This ester was converted into its hydrochloride addition salt by dissolving it in a little absolute ether and treating the solution with an excess of ethereal hydrogen chloride. A pale cream-colored solid separated. The mix ture was. cooled and the solid was collected and Additional lower alkyl 4-nitro-2-(tertiaryarhinoalkoxy benzoates which can be prepared according to the foregoing procedures include the following: ethyl 4-nitro-2-(Z-dimethylamino-lpropoxy)benzoate; isobutyl 4-nitro-2-[3-(l-pyrrolidyl)propoxylbenzoate; ethyl 4-nitro-2-[2- (2,5 dimethyl 1 pyrrolidyl)ethoxylbenzoate; methyl 4 nitro 2 (4 dimethylaminobutoxy) benzoate; n-propyl 4-nitro-2-[2-(di-n-butylamino) ethoxylbenzoate; n-butyl 4-nitro-2-[3 crystallized twice from absolute ethanol.

(2) 4-nitro-2-(tertiary-aminoalkory) benzoic acids These acids are prepared by saponification of the corresponding lower alkyl esters as illustrated by the following examples;

4-m'tro-2- (Z-diethylaminoethoxy) benzoic acid was prepared as follows: A mixture containing 15 g. of ethyl 4-n'itro-2-'(Z-diethylaminoethoxy) benzo'ate monohydrochloride, 18.3 g. of sodium carbonate, 100 m1. of water and 100 ml. of 95% ethanol was refluxed for four hours. The ethanol was removed by distilling in vacuo and the remaining aqueous solution was diluted with water, acidified with concentrated hydrochloric acid and cooled, whereugon some solid separated. The mixture was saturated with ammonium sulfate, whereupon more solid separated. This ,solid. was collected and recrystallized three times from methanol, yielding as pale yellow needles, 4-nitro-2- (2-diethylaminoethoxy) benzoic acid in the form of its monohydrochloride, M. P. 212.5- 213.9 C. (cor.).

AnaZ.-Calcd. for C13H18N205HC1I C. 48.98; H, 6.01; 01, 11.12; Nno 4.39. Found: C, 49.28; H, 6.13; 'Cl,.10.92; NNo,, 4.21.

, Nh'O stands for nitro nitrogen as determined by titration with standard titanous chloride in glacial acetic acid solution.

4-nitro-2- (Z-diethylaminoethoxy) benzoic acid is also obtained following the above procedure but using, in place of ethyl 4-nitro-2-(2-diethyl- 'aminoethoxy) benzoate hydrochloride, the correnitro-2-[3-(2 methyl 1 piperidyl) propoxylbenzoate, methyl 4-nitro-2-[2- (4-morpholinyl) ethoxylbenzoate, ethyl 4 nitro-2-[3-(4-morp-holinyl)-propoxy]benzoate or ethyl 4-nitro-2- [2-.(2,6-dimethy1 1 p'iperidyl) ethoxylbenzoate,

each either in the form of its free base or hydrochlorideaddition salt, there is obtained, respectively, ,4-nitro-2- 3- (2-methyl-l-piperidyl) propoxylbenzoic acid, 4-nitro-2-[2e(4-morpholinyl) ethoxy] benzoic acid, 4-nitro-2- [3- (4-mor- 'pholinyl)propoxylbenzoic acid or 4-nitro-2-[2- (2,6-.dim,ethyl-l-piperidyl) ethoxylbenzoic acid.

When the above procedure wasfollowed but using 113 g. of ethyl 4-nitro-2-[3-(l-piperidyl)- propoxylbenzoate monohydrochloride, 128.5 g. of sodium carbonate, 800 ml. of water and 800 ml. of 95% ethanol, and a reflux period of twentyone hours,'therel was obtained 4-nitro-2-[3-(1- piperidyhpropoxylbenzoic acid monohydrochloride, M. P. 216.8-21'7.5 C. (con), when re AnaZ.Calcd. for C15H10N20'5'HC1Z C1,. 10.23; ND, 8.16. Found: Cl, 10.09; No, 8.17.

4-nitro-2 (2 dimethylaminoethoxy)benzoic acid in the form of its'monohydrochloride salt was prepared following the above procedure but using 15 g.,of ethyl 4-nitro-2-(Z-dimethylaminoethoxy)benzoate, 169g. of sodium carbonate, 100 m1. of water and 100 m1. of 95% ethanol, and a reflux period of sixteen hours. The product, '4- nitro'-2-(Z-dimethylaminoethoxy) -benzo ic acid monohydrochloride, melted at 2080-2096 C. (con) when recrystallized three times from absolute ethanol.

AnaZ.-Calcd. for C1lHl4N205'HC1I C1, 12.20; NNo 4.82. Found: Cl, 12.06; NNo 4.70.

Additional 4-nitro-2- (tertiary-aminoalkoxy) benzoic acids which can be prepared according to the foregoing procedure include the following: 4-nitro-2-(2 dimethylamino- 1 propoxy)benzoic acid; 4-nitro-2-[3-(1-pyrrolidyl)propoxylbenzoic acid; 4-nitro-2-[2-(2,5-dimethyl-'1-pyr-' rolidyDcthoXyJbenZOic acid; 4-nitro 2-(4-dimethylaminobutoxy)benzoic acid; 4-nitro-2-[2- (di-mbutylamino) ethoxylbenzoic acid; 4-nitro- 2-[3-(4 methyl 1 piperidyl) propoxylbenzoic acid; 4-nitro 2 2- (3 ethyl-l-piperidyD- ethoxylbenzoic acid; 4-nitro-2-[3-(2-methyl-1- pyrrolidyl) propoxylbenzoic acid; and the like.

(3). Tertiary-aminoalkyl 4 nitro 2 (tertiaryaminoalkoayz benzoates These esters are prepared preferably by reacting the corresponding 4-nitro-2-(tertiary-aminoalkoxy benzoic acids with 'a tertiary-aminoalkyl halide, preferably the chloride, as illustrated by the following examples.

2-diethylaminoethy1' 4-nitro-2 (2 diethylaminoethoxy benzoate was prepared as follows: A mixture containing 15.9 g. of 4-nitro-2-(2- diethylaminoethoxy)benzoic acid monohydrochloride, 8.1 g. of 2-diethylaminoethyl chloride and 200 m1. of isopropanol was refluxed for seven hours and then allowed to stand at room temperature overnight. Rosettes of white needles which has separated were collected. The filtrate was concentrated in vacuo, cooled and diluted with ethyl "acetate, whereupon a small amount of additional White solidseparated. This solid was collected and combined with the first crop of white needles; the combined crops were dissolved in a little water; and the aqueous solution was treated with an excess of 35% aqueous sodium hydroxide solution. The mixture was saturated with sodium chloride and was extracted exhaustively with ethyl acetate. The ethyl acetate extract was dried over anhydrous .cal-

cium sulfate and the ethyl acetate was removed by distilling under reduced pressure, thereby yielding as 'a straw colored mobile oil, 2-diethylaminoethyl 4'-nitro-2 (2 diethylaminoethoxybenzoate." This esterwas converted into its dihydrochloride salt by dissolving it in a minimum amount of ethyl acetate and adding to the solution an excess of ethereal hydrogen chloride.

There separated an oil which solidified when cooled and. triturated. The solid was collected and recrystallized three times from absolute ethanol, yielding 2-diethylaminoethyl 4-nitro- 2- (Z-diethylaminoethoxy) benzoate dihydrochloride, M. P. 193.0-193.9 C. (cor.).

Anal.Calcd. for C19H31N305'2HC11 C, 50.22; H, 7.32; Cl, 15.61. Found: C, 50.44; H, 7.33; Cl,

Following the above procedure but using, in place of 4-nitro-2-(diethylarninoethoxy)benzoic acid monohydrochloride, 4-nitro-2-[3-(2-methyl-l-piperidyl)propoxylbenzoic acid, 4-nitro-2- [2- (4-morpholinyl) ethoxy] -benzoic acid, 4-nitro-2- l3- (4-morpholinyl) propoxy] benzoic acid or 4- nitro 2 [2 (2,6 dimethyl 1 piperidyl) ethoxylbenzoic acid, each either in the form of its free base or its monohydrochloride addition salt, there is obtained, respectively, 2-diethylaminoethyl 4-nitro-2- [3-2-methyll-piperidyl) propoxylbenzoate, 2-diethylaminoethyl1 4-nitro- .in water.

ll 2- [2- (4-morpholinyl) -ethoxy] benzoate, 2-diethylaminoethyl 4-nitro-2- [3- (4-morpholinyl) propoxyl-benzoate or Z-diethylaminoethyl 4-nitro- 2 [2 (2,6 dimethyl 1 piperidyl) ethoxylbenzoate.

3- (l-piperidyl) propyl 4-nitro-2- (2-diethylaminoethoxy)benzoate, was prepared as follows: A

mixture containing 31.9 g. of 4-nitro-2-(2-diethylaminoethoxy)benzoic acid monohydrochloride, 19.4 g. of 3-(l-piperidyl)propyl chloride and 600 ml.of isopropanol was refluxed for twenty-three hours. The reaction mixture was cooled, diluted with water and the isopropanol was removed by distilling in vacuo. The remaining aqueous solution Was cooled, made alkaline with aqueous sodium hydroxide solution and the liberated oil was taken up with ethyl acetate. The aqueous layer was saturated with sodium chloride and extracted two additional times with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous calcium sulfate. A small amount of solid that separated from the dried ethyl acetate solution was filtered off and the mixture was cooled and diluted with ethyl acetate. The solid was collected and was recrystallized four times from absolute ethanol, yielding 3 (1 -'piperidyl)propyl 4 nitro 2 (2 diethylaminoethoxy)benzoate dihydrochloride, M. P. 214.4-215.2 C. (cor.).

NNQ,, 2.98. Found: 01,1460; NNo,, 3.12.

Following the foregoing procedure but using, in place of 4-nitro-2-(2-diethylaminoethoxy)benzoic acid monohydrochloride, 4-nitro-2-(2-dimethylaminoethoxy)benzoic acid, 4-nitro-2-[3- (Z-methyl-l-piperidyl)propoxylbenzoic acid, 4- nitro 2 [2 (2,6 dimethyl 1 piperidyDethoxylbenzoic acid or 4-nitro-2-[3-(4-morpholinyl) propoxylbenzoic acid, each either in the form of its free base or its hydrochloride addition salt, there is obtained, respectively, 3-(1-piperidyl) propyl 4-nitro-2- (Z-dimethylaminoethoxy) benzoate, 3 -(l piperidyDpropyl 4 nitro-2-[3 -(2- methyl-l-piperidyl) propoxylbenzoate, 3- (l-piperidyl) propyl 4-nitro-2- [2- (2,6-dimethyl-l-piperidyl) ethoxylbenzoate or 3- (1piperidyl)propyl 4 nitro-Z- [3 (4-morpholinyl)propoxylbenzoate.

2 (4 morpholinyl) ethyl 4 nitro 2 (2- diethylaminoethoxy)benzoate was prepared as follows: A mixture containing 31.9 g. of 4-nitro- '2- (2 diethylaminoethoxy) benzoic acid monohydrochloride; 18 g. of 2-(4-morpholinyl) ethyl chloride and 600 ml. of absolute ethanol was refluxed for twenty hours, filtered while hot and then concentrated in vacuo to remove the solvent.

"The oily residue crystallized when triturated with ,dry acetone. This crystalline solid was collected, washed with ethyl acetate and dissolved The aqueous solution was made alkaline with ammonium hydroxide and the oil that separated was taken up with ethyl acetate. .The

aqueous layer was saturated with sodium chloride and extracted two additional times with ethyl acetate. The combined ethyl acetate extracts ,were dried over anhydrous calcium sulfate. Some solid material that separated from the dried ethyl acetate solution was filtered and the filtrate was concentrated in vacuo to yield a small amount of oily product, 2-(4-morpholinyl) ethyl 4-nitro-2- (2-diethylaminoethoxy) benzoate. The oily product was converted into its dihydrochloride by dissolving it, with warming, in a minimum quantity of ethyl acetate, filtering to remove some insoluble material, cooling the filtrate and adding thereto an excess of ethereal hydrogen chloride, whereupon an oil separated. The mixture was diluted with absolute ether to insure complete precipitation. The solvents were removed by decantation and the oily material crystallized when'triturated with dry acetone. The crystalline product was recrystallized three times from absolute ethanol, yielding 2 (4 morpholinyl) ethyl 4 nitro 2 (2 diethylaminoethoxy)benzoate dihydrochloride, M. P. 2l7.0-218.0 C. (con).

AnaL-Calcd. for C19Hz9N303'2HC]: Cl, 15.14; NNO, 2.99. Found: 01, 14.90; NNQ, 2.95.

3 (1 piperidyDpropyl 4 nitro 2 [3 ('1- piperidyl)propoxylbenzoate wasprepared as follows: A mixture containing 34.5 g. of 4-nitro- 2- [3-(1-piperidyl) propoxy] benzoic acid monohydrochloride, 19.4 g. of 3-(1-piperidyl)propyl chloride and 600 m1. of isopropanol was refluxed for twenty-four hours and then evaporated under reduced pressure to remove the solvent, thereby yielding a solid residue. The solid was suspended in ethyl acetate, filtered and washed with ethyl acetate. This solid was dissolved in water, the solution was treated with concentrated ammonium hydroxide and the oil that separated was extracted with ether. The ether extract was dried over anhydrous calcium sulfate. Removal of the ether under reduced pressure yielded the oily product, 3-(1-piperidyl)propyl 4-nitro 2-[3- (l-piperidyl)propoxylbenzoate. This ester was converted into its dihydrochloride salt as follows: To a solution of 23 g. of 3-(1-piperidyl)propyl 4-nitro-2- [3- l-piperidyl) propoxy] benzoate dissolved in a minimum amount of ethyl acetate was added an excess of ethereal hydrogen chloride, whereupon a white solid separated. The mixture Was diluted with ethyl acetate and allowed to stand for one hour. The solid was filtered, washed with ethyl acetate and then recrystallized once from absolute ethanol-isopropanol and once from absolute ethanol, yielding as rosettes of cottony white needles, 3 (1 piperidyDpropyl 4 nitro 2 4 [3 (1- piperidyl) propoxylbenzoate dihydrochloride, M. P. 2l3.0-214.1 C. (con).

AnaL-Calcd. for C23H35N3O5'2HC1: Cl, 14.00; Nivo 2.77. Found: C], 13.70; NN02, 2.88.

Additional tertiary aminoalkyl 4 nitro 2- (tertiary-aminoalkoxy)-benzoates which can be prepared according to the foregoing procedure include the .following: 4-diethylaminobutyl 4- nitro 2 (2 dimethylamino 1 propoxy)- benzoate; 1 pyrrolidyl)propoxylbenzoate; 2 dimethylaminoethyl 4 nitro 2 [2 (2,5 dimethyl- 1 pyrrolidyl)ethoxylbenzoate; 3 (2 -'methyl- 1 pyrrolidyhpropyl 4 nitro 2 (4 dimethylaminobutoxy) benzoate; 2- (2,6-dimethyl l piperidyDethyl 4 nitro 2 [2 (di nbutylamino) ethoxy] benzoate; butylaminoethyl 4 nitro 2 [3 (4 methyl- 1 piperidyl) propoxylbenzoate; 2 (3 ethyl- 1 piperidyl) ethyl 4 nitro 2 [2 (3 ethyll-piperidyl) ethoxylbenzoate; 3- (4-morpholinyl) propyl 4 nitro 2 [3 (2 -methyl 1 pyrrolidyl)propoxylbenzoate; and the like. Y

3- l-pyrrolidyl) propyl 4-nitro-2- [3- .2- (tertiary-aminoalkoxy) benzoates.

. ethoxylbenzoate;

Tertiary-aminoallcyl 4-amz'no-2-(tertiaryaminoalkory) benzoates These esters are prepared by reduction of the corresponding tertiary aminoalkyl 4 nitro- This procedure is illustrated as follows.

2 diethylaminoethyl 4 amino 2 (2 diethylaminoethoxy)benzoate is prepared as follows: To a solution of 4.5 g. of. 2-diethylaminoethyl 4-nitro-2- (2-diethylaminoethoxy') benzoate 'dihydrochloride in 150 ml. of ethanol is added 0.3 g. of platinum oxide monohydrate, and the mixture is treated with hydrogen at 50 lbs. per square inch of pressure at room temperature. The reduction is rapid and exothermic.

The catalyst is filtered oil and the filtrate is evaporated to dryness under reduced pressure, yielding a solid residue of 2-diethylaminoethyl,4-amino- 2-(2-diethylaminoethoxy)benzoate in the form of its dihydrochloride. This product is recrystal- "lized from absolute ethanol.

Following the above procedure but using, in

place of 2-diethy1aminoethy1 4-nitro-2-(2-diethylaminoethoxy) benzoate dihydrochloride, 3-

(1-piperidyl propyl 4-nitro-2- (Z-diethylaminoethoxy) benzoate, 2- 4-morpholinyl) ethyl 4-nitro 2 (2 diethylaminoethoxy)benzoate, 3- (1 piperidyDpropyl 4 nitro 2 [3 (1 piperidyl)propoxylbenzoate, 2-diethylaminoethyl 4 nitro 2 [3 (2 methyl 1 piperidyl) propoxylbenzoate, Z-diethylaminoethyl 4-nitro- 2 [2 (4 morpholinyl)ethoxylbenzoate, 2- diethylaminoethyl 4-nitro-2- [3- (4-morpholinyl) propoxylbenzo-ate or 2-diethylaminoethyl 4-nitro 2 [2 (2,6 dimethyl 1 piperidyl) ethoxylbenzoate, each either in its free base form .or in the form ofits dihydrochloride addition ethoxy] benzoate.

Additional tertiary aminoalkyl 4 amino 2- (tertiary-aminoalkoxy)benzcates which .can be prepared according to the foregoing procedure include the following: 4-diethylaminobutyl 4- amino 2 (2 dimethylamino 1 propoxy) benzoate; 3-(1-pyrrolidyl)propyl 4-amino-2-[3- (1 pyrrolidyl)propoxylbenzoate; 2 dimethylaminoethyl 4 amino 2 [2 (2,5 dimethyll pyrrolidyl)ethoxylbenzoate; 3 (2 methyl- 1 pyrrolidyl) propyl 4 amino-2 (4 dimethylaminobutoxy)benzoate; 2 (2,6 dimethyl 1- piperidyl) ethyl 4-amino-2- [2- (di-n-butylamino) ethoxylbenzoate; 2-di-n-butylaminoethyl amino 2 [3 (4 methyl l piperidyl) propoxy] benzoate; 2- (3-ethyl-1-piperidyl) ethyl 4 amino 2 [2 (3 ethyl 1 piperidyl) 3- (4-morpholinyl) propyl 4- amino 2 [3 (2 methyl 1 pyrrolidyl) propoxyl benzoate; and the like.

(5) Ter'tiary-aminoalkyl 4-mtro-2- (tertiaryaminoalkoxy)benzoate quaternary ammonium salts These compounds are prepared by treating the I corresponding tertiary-aminoalkyl 4-nitro-2- (tertiary-aminoalkoxy).benzoates with an alkyl or benzyl ester of an inorganic or organic acid of the type described hereinabove. Illustrations of the reaction follow.

- 2.- diethylaminoethyl 4 nitro 2 (2 diethylaminoethoxy)benzoate dimethiodide was prepared as follows: To a solution of 4.8 g. of 2-diethylaminoethyl 4-nitro-2-(Z-diethylaminoethoxy benzoate dissolved in .125 ml. of ethyl acetate was added ml. of methyl iodide, whereethanol containing a small quantity of water,

thereby yielding as'pale yellow needles, Z-diethylaminoethyl 4 nitro 2 (2 diethylaminoethoxy benzoate dimethiodide, M. P. 212.0- 213.0 C. (cor.). I

' 5.61; I, 38.15. Found: C, 37.98; H, 5.67; I, 38.30..

4 nitro -'2 (2 (4 morpholinybethoxy] benzoate, 2-diethylaminoethyl 4-nitro -2-[3-4- morpholinyl)propoxylbenzoate or 2 -'diethyl aminoethyl 4 nitro 2'- [2 (2,6 dimethyll-piperidyl)ethoxylbenz oate, there is obtained, respectively, 2-diethylaminoethyl .4-nitro-2-[3- (2 methyl 1 piperidyl)propoxylbenzo-ate' dimethiodide, 2-diethylaminoethyl 4-nitro-2-[2- (4-morph0linyl) ethoxyl benzoate dimethiodide, 2- diethylaminoethyl 4-nitro-2- [3- (4-morpholinyl) propoxylbenzoate dimethiodide or Z-diethyl- .aminoethyl- 4 nitro 2 [2 (2,6 dimethyll -piper idyl) ethoXyl benzoate dimethiodide.

3 (1-. piperidyDpropyl 4 nitro 2 (2 diethylaminoethoxy) benzoate dimethiodide was ob- The solution be- The mixture was then. allowed to stand at room temperature overnight. The supernatant liquid was decanted from a. red semisolid material that had separated and the semisolid material was triturated with ethanol at room temperature, whereupon complete crystallization resulted.

The crystalline product was collected and recrystallized five times from 95% ethanol, whereupon there was obtained as yellow-orange needles,

- 3,- l p-iperidyl) propyl 4-nitro-2- (2-diethylaminoplace of 3-(1 -piperidyl) propyl 4-nitro-2- (2-di- ,ethylaminoethoxy) benzoate, 3- l-piperidyl) propyl 4 nitro-2- (Z-dimethylaminoethoxy) benzoate,

l (6). Tertiary-aminoalkyl piperidyl) propoxylbenzoate, 3- (l-piperidyl) propyl 4-nitro-2- [2- 2,6-dimethyl-l-piperidyl) ethoxylbenzoate, 3- (l-p-iperidyl) propyl 4-nitro-2- [3- (4-morp-holinyl) proproxy] benzoate or 2- (4- morpholinyl) ethyl 4 nitro 2 (2 diethylaminoethoxy)benzoate, there is obtained, respectively, 3 (1 piperidyl) propyl 4 nitro 2 (2- dimethylaminoethoxy)benzoate dimethiodide, 3- (I-piperidyl) propyl 4-nitro-2-[3-(2-methyl 1- piperidyl)propoxylbenzoate dimethiodide, 3-(1- 'piperidyl) propyl 4-nitro-2- [2- (2,6-dimethyl-1- piperidyl) ethoxylbenzoate dimethiodide, 3-(1- piperidyl) propyl 4-nitro-2- [3- (4-morpholinyl) propoxylbenzoate dimethiodide or 2- (4-morpholinyl) ethyl 4 nitro 2 (2 diethylaminoetho xy)benzoate dimethiodide.

2- (2-methyl-1-piperidyl) ethyl 4-nitro-2- (2-di- 'ethy'laminoethoxy)benzoate dimethiodide was prepared according to the procedure described above for the preparation of 2-diethylaminoethyl 4 nitro --2 (2 diethylaminoethoxy)benzoate dimethiodide but using 6 g. of 2-(2-methyl-1- piperidyDethyl 4 nitro 2 (2 diethylaminoethoxy)benzoate, 200 ml. of ethyl acetate and ml. of methyl iodide. The product melted at 201.1-202.9 C. (corL) when recrystallized from absolute ethanol containing a'small amount of water.

ArrLal.-Ca1Cd for C23H39I2N3O5: 2.03. Found: I, 36.45; Nno 2.17.

, 3-(l-piperidyl)propyl 4-nitro-2-[3-(l-piper- 'idyDpropoxylbenzoate dimethiodide was prepared according to the above procedure but using I, 36.71; NNO

5 g. of 3-(l-piperidyDpropyl 4-nitro-2-[3-(1- "methiodide; 2-dimethylaminoethyl 4-nitro-2- [2- (2,5 dimethyl 1 pyrrolidyl) ethoxylbenzoate dimethiodide; 3- (2-methyl-l-pyrrolidyl) propyl 4-nitro-2- l-dimethylaminobutoxy) benzoate dimethiodide; 2- 2,6 -dimethyll-piperidyl) ethyl 4- 'nitro 2 [2 (di n butylamino)ethoxy]benzoate dimethiodide; 2-di-n-butylaminoethyl 4- nitro 2 [3 (4 methyl 1 piperidyl) pro- ,poxy] benzoate dimethiodide; 2- (3-ethyl-1-piperj idyl) ethyl 4-nitro-2 [2- (B-ethyl-l-piperidyl) eth- .Xy]benzoate dimethiodide; 3-(4-morpholiny1)- propyl 4-nitro-2- [3- (2-methyl-1-pyrrolidyl) propoxylbenzoate dimethiodide; and the like.

4-am2'no-2- (tertiaryaminoalkoxwbenzoate quaternary ammonium salts j These compounds are prepared preferably by reducing the above described tertiary-aminoalkyl 4-nitro-2- (tertiary-aminoalkoxy) benzoate quaternary ammonium salts. The reduction is carried out preferably by catalytic hydrogenation methods, as illustrated by the following examples.

2-diethylaminoethyl 4-amino-2-(2-diethylaminoethoxy) benzoate dimethiodide was prepared as follows: A mixture of 5 g. of 2-diethylaminoethyl 4- nitro 2 (2 diethylaminoethoxy)benzoate dimethiodide,'200 mg. of platinum oxide monohydrate, m1. of absolute ethanol and 35 ml. of water was treated with hydrogen underreduced pressureat 50 C. until uptake of hydrogen ceased. The catalyst was filtered off and washed with absolute ethanol. The filtrate was evaporated to dryness in vac-uo. The residue was then treated with 300 ml. of ethyl acetate and the ethyl acetate was removed by distilling in vacuo. This procedure was repeated again with another 300( ml. of ethyl acetate and then once with 300 ml. of dry acetone. The remaining semisolid material crystallized as a white'solid when triturated with absolute ethanol. The solid was collected and recrystallized three times from absolute ethanol to yield 2-diethy1aminoethyl 4-amino-2-(2- diethylaminoethoxy) benzoate dimethiodide, M. P. 2105-2119 C'. (cor.). "'AnaL-Calcd. for C21H39I2N203Z C, 39.69; H, 6.19; I, 39.97. Found: C, 39.58; H, 6.09; I, 39.73. When the above procedure is followed but using, in place of Z-diethylaminoethyl 4-nitro-2- (2 diethylaminoethoxy) benzoate dimethiodide, the corresponding 2-diethylaminoethyl 4-nitro- 2- (Z-diethylaminoethoxy) benzoate dimethobromide, diethochloride, d'i-n-p-ropiodide, dibenzochloride or di-etho-para-toluenesulfonate, there is obtained, respectively, 2-diethylaminoethyl-4- amino- 2 (2 diethylaminoethoxy) benzoate dimethobromide, diethochloride, di-n-propiodide, dibenzochloride or di-etho-para-toluenesulfonate. Following the above procedure but using, in place of Z-diethylaminoethyl 4-nitro-2-(2-diethylaminoethoxy) benzoate dimethiodide, 3-(1- piperidyl) propyl 4-nitro-2- (Z-diethylaminoethoxy) benzoate dimethiodide, 3-(1-piperidy1) propyl 4 nitro 2 [3-(2-methyl-1-piperidyl) propoxylbenzoate dimethiodide, 2-(4-morpholinyl) ethyl 4-nitro-2- (2-diethy1aminoethoxy) benzoate dimethiodide, 2-(2-methyl-1-piperidyl)ethyl 4- nitro-2- (2-diethylaminoethoxy) benzoate dimethiodide, 3- l-piperidyl) propyl 4-nitro-2- [3- (1- 'piperidyl)propoxylbenzoate dimethiodide, 2-diethylaminoethyl 4-nitro-2- [3- (Z-methyl-l-piperidyDpropoxylbenzoate dimethiodide, 2-diethylaminoeth'yl 4 nitro -'2- [2-(4-morpholinyl) ethoxylbenzoate dimethiodide, Z-diethylaminoethyl 4 nitro-z- [3- (4-morpholinyl) propoxy] benzoate dimethiodide or 2-diethylaminoethyl 4 -nitro-2- [2 (2,6 dimethyl-l-piperidyl)ethoXy] benzoate dimethiodide, there is obtained, respectively, 3- (l-piperidyl) propyl 4-amino-2- (Z-diethylaminoethoxy) benzoate dimethiodide, 3-(1-piperidyl) propyl 4-amino-2- [3- (2-methyl-1 -piperidyl) propoxylbenzoate dimethiodide, 2-(4-morpholinyl) ethyl 4-amino-2-(2-diethy1imanoethoxy) benzoate dimethiodide, 2-(2-methyl-l-piperidyl) ethyl 4-amino-2- (Z-diethylaminoethoxy) benzoate dimethiodide, 3- l-piperidyl) propyl 4-amino-2- [3- (l-piperidyl) propoxylbenzoate dimethiodide, 2- diethylaminoethyl 4-amino-2- [3- (2-methyl-1-piperidyl) propoxylbenzoate dimethiodide, 2-diethylaminoethyl 4-amino-2- [2- (4-morpholinyl) ethoxylbenzoate dimethiodide, Z-diethylaminoethyl 4-amino-2- 3- (4-morpholinyl) propoxy] benzoate dimethiodide or 2-diethylaminoethyl 4-amino-2- [2 (2,6 dimethyl-l-piperidyl) ethoxylbenzoate dimethiodide. 7

Additional tertiary-aminoalkyl 4 amino- 2 (ter-tiary aminoalkoxy) benzoate dimethiodides which can be prepared according to the foregoing procedure includes the following: 4-diethylaminobutyl 4 amino-2-(2-dimethylaminol-pr'opoxy) benzoate dimethiodide; 3-(1-pyrrolaeeaaea;

17 idgllpropyl 4- amino- 2 EB-(l-pyrrolidybpropoxyJ-benzoate :dimethiodide; 2-dimethylaminoethyl 4-.ammo-.2-'[2-;2,5 -dimethyl--l-;pyrrolidyl)- ethoxylbenzoate dimethiodide; 3-(2-methyl-lpyrrolidyl) propyl 4-amino2- l-dimethylaminobutoxy) benzoate dimethiodide; 2-(2,6-dimethyll-piperidyl) ethyl 4-amino 2 [2 (di-n-butyl- -amino ethoxylbenzoate dimethiodide; 2-di-nbutylaminoethyl 4 amino 2 [3-(4-methyl-1- piperidyl) propoXYJ benzoate dimethiodide; 2 3- ethyl-l-pipe idyl) ethyl 4-amino-2- [2- (S-ethyl-lpiperidyl) ethoxylbenzoate dimethiodide; 3- (4- morpholinyl) propyl 4-am'ino-2-[3- (2-methyl-1- pyrrolidyl)propoxylbenzoate dimethiodide; and the like.

We claim: a 1. A quaternary formula COO-Y-NRaRa where Z is a member of the group consisting of nitro and amino, X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms, .NRR1 and NR2R3 are each members of the group consisting of dialkylamino, l-piperidyl, (lower alkylated)-l-piperidyl, l-pyrrolidyl, (lower-alkylated) 1 pyrrolidyl and 4- morpholinyl, R5 is a member of the group consisting of a lower alkyl radical and a benzyl radical, and An is a non-toxic anion of a strong acid.

2. A quaternary ammonium salt of a dialkylaminoalkyl' 4-.amino 2 (dialkylaminoalkoxy') benzoate having the formula where and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms, R5 is a lower alkyl radical and An is a non-toxic anion of a strong acid.

3. A quaternary ammonium salt of a diethylaminoalkyl -amino 2 (diethylaminoalkoxy) benzoate having the formula where X and Y are each lower alkylene radicals Whose two free valence bonds are on difierent carbon atoms, R is a lower alkyl radical and An is a non-toxic anion of a strong acid.

4. A quaternary ammonium salt of a dialkylaminoalkyl -nitro 2 (dia1kylaminoalkoxy)- benzoate having thejormula ammonium salt having the where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms, Ra ls a lower alkyl radical and An is a non-toxic anion of a strong acid.

5. A quaternary ammonium salt of a diethylaminoalkyl 4 nitro .2 (diethylaminoalkoxy)- benzoate having the formula M benzoate having the. formula where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms, NRzRs is a (lower alkylated-lpiperidyl radical, R5 is'a lower alkyl radical and An is a non-toxic anion of a strong acid.

8. A quaternary ammonium salt of a tertiaryaminoalkyl A nitro d a sv m no oxyl benzoate hav n the ior ula where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms, NR2R3 is a Z-methyl-l-piperidyl radical, R5 is a lower alkyl radical and An is a non-toxic anion of a strong acid.

9. A quaternary ammonium salt of a tertiaryaminoalkyl 4 nitro 2 (tertiary aminoalkoxy) benzoate having the formula 3? o-x-mm,

, 1'15 OOY-NR:R;

where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms, N'RR1 and NRzRs are each l-piperidyl radicals, R5 is a lower alkyl radical and An is a non-toxic anion of a strong acid.

10. A process of preparing a quaternary ammonium salt having the formula u O-X-ILTRR:

, R 11 COO-Y-IQRaRa where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms, NRR1 and NRzRs are each members of the group consisting of dialkylamino, 1 piperidyl, (lower alkylated) 1 piperidyl, l-pyrrolidyl, (lower alkylated) -l-pyrrolidyl and 4 -morpholinyl, R5 is a member of the group consisting of a lower alkyl radical and a benzyl radical and An is a non-toxic anion of a strong acid, which comprises treating the corresponding tertiary -'aminoalkyl 4 nitro 2 (tertiary aminoalkoxy benzoate with an ester having thev formula Rs- -An and treating the resulting tertiary aminoalkyl 4 nitro 2 (tertiary aminoalkoxy) benzoate quaternary ammonium saltwith a reducing agent efiective to reduce nitro groups to amino groups.

11. A process of preparing a quaternary ammonium salt of a dialkylaminoalkyl 4-amino-2- (dialkylaminoalkoxy)benzoate having the formula a r Y -XN(lower alkyl R 11 G( )'0-YN(lower alkyl);

where X' and Y are each lower alk'ylene radicals whose two free valence bonds are on different carbon atoms, R5 is a lower alkyl radical and An is a non-toxic anion of a strong acid, which comprises treating the corresponding dialkylaminoalkyl 4-nitro-2- (dialkylaminoalkoxy)benzoate with an ester having theformula R5-An and treating the resulting dialkylaminoalkyl 4-nitro-2- (dialkylaminoalkoxy) benzoate quaternary ammonium salt with a reducing agent effective to reduce nitro groups to amino groups.

V V 12. A process of preparing a quaternary'ammonium salt of a diethylaminoalkyl 4-amino-2- (diethylaminoalkoxy)benzoate having the formula where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbons atoms, R5 is a lower alkyl radical and An is a non-toxic anion of a strong acid, which aminoalkyl 4-nitro-2- (diethylaminoalkoxy) benzonate with an ester having the formula R5An and treating the resulting diethylaminoalkyl 4-nitro-2- (diethylaminoalkoxy) benzoate quaternary ammonium salt with a reducing agent effective to reduce nitrogroups to amino groups.

13. A process of preparing a quaternary ammonium salt having the formula where X and Y are each lower alkylene radicals whose two free valence bonds are on' different carbon atoms, NRR1 and NRzRs are each members of the group consisting of dialkylamino, l-piperidyl, (lower alkylated) -1-piperidyl, 1- pyrrolidyl, (lower alkylated) -1-pyrrolidyl and a-morpholinyl, R5 is a member of the group consisting of a lower alkyl radical and a benzyl radical and An is a non-toxic anion of a strong acid, which comprises treating the corresponding tertiary aminoalkyl 4 nitro 2 (tertiary-aminoalkoxy) benzoate with an ester having the formula R5An.

14. A process of preparin a quaternary ammonium salt of a dialkylaminoalkyl 4-nitro-2- (dialkylaminoalkoxy)benzoate having the formula 7 21 ,(diethylaminoalkoxy)benzoate having the f o rmula where X and Y are each lower alkylene radicals whose two free valence bonds are on difierent carbon atoms, R is a lower =-a1kyl radical and An is ,a non tog-ic anion of a strong acid, which comprises treating the corresponding diethylaminoalkyl 4-n-itr-o-2-(diethylaminoalkoxy)benzoate with an ester having the formula Its-An.

16. A process of preparing a quaternary ammonium salt of a tertiary-aminoalkyl 4-nitro-2- (dialkylaminoalkoxy)benzoate having the formula where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms, NR2R3 is a l-piperidyl radical, R5 is a lower alkyl radical and An is a non toxic anion of a strong acid, which comprises treating the corresponding tertiary-aminoalkyl 4-nitro- 2-(dialkylaminoalkoxy) benzoate with an ester having the formula R5An.

17. A process of preparing a quaternary ammonium salt of a tertiary-aminoalkyl 4-nitro-2- (dialkylaminoalkoxy)benzoate having the formula where X and Y are each lower alkylene radicals whose two free valence bonds are on different carbon atoms, NRzRs is a (lower alkylated) -1- piperidyl radical, R5 is a lower alkyl radical and An is a non-toxic anion of a strong acid, which comprises treating the corresponding tertiaryaminoalkyl 4-nitro-2- (dialkylaminoalkoxy) benzoate with an ester having the formula Rs-Al'l.

18. A process of preparing a quaternary ammonium salt of a tertiary-aminoalkyl 4-nitro-2- (dialkylaminoalkoxy)benzoate having the formula where Jand {3J8 each I'lower alkylene radicals whose atwo free valence ihonds are on .-,d'ifierent carbon atoms, NRzRs is a 2.-.methyl-1 -piperidylradical, R5 is a lower alkyl radical and An is a non-toxic anion of a strong acid, which comprises treating the corresponding tertiary-aminoalkyl 4-nitro-2- (dialkylaminoalkoxy)benzoate with an ester having rfzhe jprmula R5An.

19. A process of preparing a quaternary ammonium salt of a tertiary-aminoalkyl 4-nitro-2- (tertiary-aminoalkoxy') benzoate having the formula y 21. 2-diethylaminoethyl 4-nitro-2-(2-diethylaminoethoxy)benzoate dimethiodide having the formula 22. 3-(1-piperidyl) propyl 4-nitro-2- (2-diethylaminoethoxy) benzoate dimethiodide having the formula O CHaCH:N(C2Ha)n CHz-CE: C O 0 01120111011:

CH2 CHa-CH;

24 "23. 2-(2-methyl-l-pi p ridyl) ethyl 4-nitro-2- 24. 3-(1-piperidyDpropyl 4-nitro-2-[3-(1-pi- (2 diethylaminoethoxy)benzoate dimethiodide peridyDpropoxyJ-benzoate dimethiodide having having the formula the formula.

N O: I NO:

CH; CHI-CH! O CH:CH:1 T(CzH5): -O CHzCHzCHzN CHa OH: I v 10 OH; CHa-Gz GET-CH2 CHI-CH2 0001110112 om O0OHzCHzCH:N CH1 CH -C I CHr-C:

H, j 15 RAYMOND o. CLINTON.

STANLEY C. LASKOWSKI.

No references cited. 

1. A QUATERNARY AMMONIUM SALT HAVING THE FORMULA 